A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness

F. Yan, N. Shen, J. Pang, N. Zhao, B. Deng, B. Li, Yanan D Yang, Ping Yang, Julian R Molina, S. Liu

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Overexpression of DNMT1 and KIT is prevalent in lung cancer, yet the underlying molecular mechanisms are poorly understood. While the deregulated activation of DNMT1 or KIT has been implicated in lung cancer pathogenesis, whether and how DNMT1 and KIT orchestrate lung tumorigenesis are unclear. Here, using human lung cancer tissue microarrays and fresh frozen tissues, we found that the overexpression of DNMT1 is positively correlated with the upregulation of KIT in tumor tissues. We demonstrated that DNMT1 and KIT form a positive regulatory loop, in which ectopic DNMT1 expression increases, whereas targeted DNMT1 depletion abrogates KIT signaling cascade through Sp1/miR-29b network. Conversely, an increase of KIT levels augments, but a reduction of KIT expression ablates DNMT1 transcription by STAT3 pathway leading to in-parallel modification of the DNA methylation profiles. We provided evidence that KIT inactivation induces global DNA hypomethylation, restores the expression of tumor suppressor p15(INK4B) through promoter demethylation; in turn, DNMT1 dysfunction impairs KIT kinase signaling. Functionally, KIT and DNMT1 co-expression promotes, whereas dual inactivation of them suppresses, lung cancer cell proliferation and metastatic growth in vitro and in vivo, in a synergistic manner. These findings demonstrate the regulatory and functional interplay between DNA methylation and tyrosine kinase signaling in propelling tumorigenesis, providing a widely applicable approach for targeting lung cancer.

Original languageEnglish (US)
Pages (from-to)6919-6928
Number of pages10
JournalOncogene
Volume36
Issue number50
DOIs
StatePublished - Dec 14 2017

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Methyltransferases
Protein-Tyrosine Kinases
Lung Neoplasms
DNA Methylation
Carcinogenesis
Polynucleotide 5'-Hydroxyl-Kinase
Neoplasms
Phosphotransferases
Up-Regulation
Cell Proliferation
DNA receptor
Lung
DNA
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

A regulatory circuit composed of DNA methyltransferases and receptor tyrosine kinases controls lung cancer cell aggressiveness. / Yan, F.; Shen, N.; Pang, J.; Zhao, N.; Deng, B.; Li, B.; Yang, Yanan D; Yang, Ping; Molina, Julian R; Liu, S.

In: Oncogene, Vol. 36, No. 50, 14.12.2017, p. 6919-6928.

Research output: Contribution to journalArticle

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